Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:3]=1.[C:14]([O:18][C:19](=[O:31])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[C:29]#[CH:30])([CH3:17])([CH3:16])[CH3:15].N1CCCCC1>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]([O:18][C:19](=[O:31])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[C:29]#[C:30][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCS(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1cccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1
Temperature: 70 °C

Procedure:
A mixture of 1-bromo-3-(propane-1-sulfonyl)-benzene (Intermediate 5; 493 mg, 1.87 mmol), tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3, 500 mg; 1.87 mmol), dichlorobis(triphenylphosphine)palladium(II) (52 mg; 0.07 mmol) and piperidine (550 μL; 5.6 mmol) was heated at 70° C. for 18 hours. The reaction mixture was taken up in EtOAc, washed twice with citric acid (0.5 M aqueous solution) and once with brine. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording a crude, which was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as a dark orange sticky solid (640 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl.N([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]3[N:30]=[CH:29][NH:28][C:26]3=2)[N:21]=[C:20]([CH3:31])[CH:19]=1)C1C=CC=CC=1>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH:5][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]3[N:30]=[CH:29][NH:28][C:26]3=2)[N:21]=[C:20]([CH3:31])[CH:19]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CCO
Product: Cc1cc(Nc2ccc(F)c(Cl)c2)c2c(ccc3nc[nH]c32)n1

Procedure:
A mixture of 14.5 g. (0.1 m.) of 3-chloro-4-fluoroaniline, 21.7 g. (0.1 m.) of the compound of Example I, C. and 500 ml. of ethanol was refluxed overnight with stirring. It was then chilled, filtered and the product washed with ether and air-dried to give 25 g. The crude product was recrystallized from 1500 ml. of MeOH to yield 17 g.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:11][C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[C:18]([O-:21])([O-])=[O:19].[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.O.CO>[F:15][C:14]([F:17])([F:16])[C:18]([OH:21])=[O:19].[F:15][C:14]([F:17])([F:16])[C:18]([OH:21])=[O:19].[CH2:24]([N:11]1[C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[C:7]=2[CH:13]=[C:12]1[C:14]([F:17])([F:15])[F:16])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nnc2ccc3[nH]c(C(F)(F)F)cc3n12
Reactant: BrCc1ccccc1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1nnc2ccc3c(cc(C(F)(F)F)n3Cc3ccccc3)n12
Product: O=C(O)C(F)(F)F
Reaction time: 8 h

Procedure:
A solution of 1-methyl-7-(trifluoromethyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.020 g, 0.083 mmol, from Step 4) in DMF (0.5 mL) was treated with Cs2CO3 (0.054 g, 0.17 mmol) and benzyl bromide (0.010 mL, 0.084 mmol, Aldrich). After stirring overnight, the reaction was diluted with water and MeOH. The product was purified by preparative HPLC-MS (Waters SunFire C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA). Yield: (6 mg, 12%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]3[CH:13]=[CH:14][N:15]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:16]I.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[I:16][C:13]1[N:10]2[CH:11]=[CH:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][C:9]2=[N:15][CH:14]=1
Reactant: II
Reactant: c1ccc(-c2ccn3ccnc3c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Ic1cnc2cc(-c3ccccc3)ccn12
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A solution of 7-phenylimidazo[1,2-a]pyridine (1-4, 110 mg, 0.56 mmol, 1 equiv) and iodine (140 mg, 0.56 mmol, 1.0 equiv) in acetic acid (4 mL) was stirred at 23° C. for 18 h. More iodine (130 mg) was added and the mixture was stirred for 24 h at 70° C. A third portion of iodine (130 mg) was added and heating (70° C.) was continued for 2 h. The reaction mixture was basified with aqueous saturated sodium bicarbonate solution (100 mL), and the remaining iodine was quenched with addition of aqueous saturated sodium thiosulfate solution (10 mL). The mixture was extracted with EtOAc (100 mL), and the organic layer was washed with brine, dried over sodium sulfate, and then concentrated to give 3-iodo-7-phenylimidazo[1,2-a]pyridine (1-5) as a light-brown solid. 1H NMR (300 MHz, CDCl3) δ 8.18 (d, 1H, J=7.3 Hz), 7.82 (s, 1H), 7.73 (s, 1H), 7.67 (m, 2H), 7.50 (t, 2H, J=7.3 Hz), 7.42 (t, 1H, J=7.3 Hz), 7.23 (d, 1H, J=7.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:20]([O:22][CH3:23])=[S:21].Cl.N1C=CC=C[CH:26]=1>>[F:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:20](=[S:21])[O:22][CH2:23][CH3:26])[S:3][C:4]=3[CH:10]=2)=[CH:17][CH:16]=1
Reactant: Nc1nc2ccc(Oc3ccc(F)cc3)cc2s1
Reactant: c1ccncc1
Reactant: COC(=S)Cl
Agent: Cl
Product: CCOC(=S)Nc1nc2ccc(Oc3ccc(F)cc3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A suspension of 2-amino-6-(4′-fluorophenoxy)-benzothiazole (associated with 2.0 eq of KBr salt, 2.50 g, 5.02 mmol) in 10 mL pyridine was treated dropwise with methyl chlorothioformate (0.65 mL, 7.53 mmol, 01.5 eq). It was stirred at room temperature for about 1 hour, and was poured into 40 mL ice water. The mixture was acidified slowly with 1 M HCl solution. The result precipitate was filtered off, washed with water and MeOH, and dried under vacuum to give 1.18 g (65%) desired compound. LC/MS 334.9 (M+1); LC retention time 3.70 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:15])=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(C)c1C(=O)O
Product: COc1cccc(C)c1C(=O)Cl

Procedure:
A mixture of 1A (1.7 g, 10.2 mmol) and thionyl chloride (2 ml) is heated under reflux for 1 hour. The mixture is concentrated and the resulting benzoylchloride is used without further purification.
Reaction SMILES: O/[N:2]=[C:3]1/[CH2:4][C:5]2[C:10]([CH2:11]/1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.P(Cl)(Cl)(Cl)(Cl)[Cl:15].[ClH:20]>O=P(Cl)(Cl)Cl>[Cl:20][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH:11]=[C:3]([Cl:15])[N:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1ccc2c(c1)C/C(=N/O)C2
Reactant: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2cc(Cl)nc(Cl)c2c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a suspension of (E)-2-(hydroxyimino)-6-methoxy-2,3-dihydro-1H-inden-(3.60 g, 20.0 mmol) in POCl3 (120 mL), PCl5 (6.50 g, 31.3 mmol) was added at 0° C., then HCl gas was induced until the solution was saturated. The reaction mixture was stirred at 30° C. for 2 hours. The solvent was removed in vacuo and ice water was added to the residue. The precipitate was collected by filtration, washed with water (30 mL), and dried under high vacuum to give the product (4.50 g, yield 85%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29](=[O:31])[CH3:30])[C:19]2=[O:32])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10]C)[CH3:2].I[Si](C)(C)C>C(Cl)Cl.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29](=[O:31])[CH3:30])[C:19]2=[O:32])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[OH:10])[CH3:2]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Agent: C[Si](C)(C)I
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (S)—N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (1 mmol) in anhydrous CH2Cl2, is added iodotrimethylsilane (6 mmol). The mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with brine and is extracted with CH2Cl2. The CH2Cl2 is removed to give crude (S)—N-{-2-[1-(3-ethoxy-4-hydroxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide. The product is purified by recrystallization.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC=C)=[CH:9][C:8]=1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[F:27])[CH3:2].O1CCOCC1.N1CCCC1>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[F:27])[CH3:2]
Reactant: C=CCOc1ccc(OCC(=O)OCC)c(C(=O)NCc2ccc(Br)cc2F)c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: CCOC(=O)COc1ccc(O)cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
A solution of [4-allyloxy-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester (1.02 g, 2.40 mmol) and Pd(Ph3)4 (15 mg, 1.4 mol %) in a aq 1,4-dioxane solution (10 mL, 95% 1,4-dioxane) was treated with pyrrolidine (0.45 mL, 5.39 mmol) in a dropwise manner. After stirring for 2 h at room temperature, the solution was diluted with ethyl acetate and washed with aq 10% HCl, sat's aq NaCl, dried over Na2SO4, filtered and concentrated. The resulting crude solid was recrystallized with ethyl acetate and heptane to give [4-hydroxy-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester (0.780 g, 76%) as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[CH:9][N:8]([C:11]3([CH3:14])[CH2:13][CH2:12]3)[C:4]=2[N:5]=[N:6][CH:7]=1.[CH2:15]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:16]>>[CH2:15]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[C:28]([C:2]3[C:3]4[N:10]=[CH:9][N:8]([C:11]5([CH3:14])[CH2:13][CH2:12]5)[C:4]=4[N:5]=[N:6][CH:7]=3)[CH:27]=2)=[CH:24][CH:25]=1)(=[O:18])=[O:19])[CH3:16]
Reactant: CC1(n2cnc3c(Cl)cnnc32)CC1
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2F)cc1
Product: CCS(=O)(=O)c1ccc(-c2cc(-c3cnnc4c3ncn4C3(C)CC3)ccc2F)cc1
Yield: 32 %

Procedure:
Prepared according to the method described for Example 26 using 4-chloro-7-(1-methylcyclopropyl)-7H-imidazo[4,5-c]pyridazine (Preparation 97) and 2-(4′-ethylsulfonyl-6-fluorobiphenyl-3-yl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (Preparation 48) to afford the title compound as an off white solid in 32% yield, 20 mg
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O:11][C:12]([C:14]1[O:15][C:16]([S:19]([N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)=O>CO>[C:32]([O:31][C:29](=[O:30])[NH:28][CH:25]1[CH2:26][CH2:27][N:22]([S:19]([C:16]2[O:15][C:14]([C:12](=[O:11])[NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH2:23][CH2:24]1)([CH3:35])([CH3:33])[CH3:34]
Reactant: NCCc1ccccc1
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)o1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)NCCc3ccccc3)o2)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Phenethylamine (0.5 g, 4.1 mmol) was added in one portion to a stirred solution of 5-(4-tert-butoxycarbonylamino-piperidine-1-sulfonyl)-furan-2-carboxylic acid methyl ester (0.4 g, 1.0 mmol) in methanol (10 ml) at room temperature. The reaction mixture was then heated to 45° C. and stirred at this temperature overnight, after which time the mixture was concentrated. The resulting residue was dissolved in DCM (100 ml), washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.46 g, 94% yield) as a light brown solid which was taken on without further purification. δH (500 MHz, DMSO) 8.71 (t, J=5.79 Hz, 1 H) 7.13-7.38 (m, 8 H) 6.93 (d, J=7.61 Hz, 1 H) 5.75 (s, 1 H) 3.41-3.63 (m, 5 H) 2.66-2.91 (m, 5 H) 1.66-1.87 (m, 2 H) 1.25-1.47 (m, 12 H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]1([N:38]=C=NC2CCCCC2)CCCCC1.C1COCC1.CN>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][C:29]([NH:38][CH3:32])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN(CC(=O)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)CN1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reaction time: 16 h
Yield: 29.3 %

Procedure:
A solution of [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid (21.2 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) at 0° C. was treated with catalytic 4-dimethylaminopyridine (DMAP) (˜1 mg) and N,N′-dicyclohexylcarbodiimide (DCC) (11.3 mg, 0.055 mmol) followed 5 min later by a 2 M THF solution of methylamine (30 μL, 0.06 mmol). The reaction mixture was stirred for 16 h, evaporated, and purified by silica gel flash chromatography with 50% EtOAc/hexane, then 100% EtOAc, then 5% MeOH/EtOAc as eluant to afford the title compound as an oil (6.4 mg, 29%). LC/MS (Method A) 5.09 min, [M+1]+ 438.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=2)[CH:6]=[N:5]1)(=O)C.[CH:14]1([CH2:17][NH:18][C:19](=[O:35])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:16]C1.[C:36](=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC>[CH:17]1([NH:18][C:19](=[O:35])[C:20]2[CH:21]=[CH:22][C:23]([CH3:36])=[C:24]([C:10]3[CH:11]=[C:12]4[C:7]([CH:6]=[N:5][NH:4]4)=[CH:8][CH:9]=3)[CH:25]=2)[CH2:14][CH2:16]1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)n1ncc2ccc(Br)cc21
Reactant: CC1(C)OB(c2cccc(C(=O)NCC3CC3)c2)OC1(C)C
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2cn[nH]c2c1
Reaction time: 4 h

Procedure:
A mixture of 1-acetyl-6-bromo-1H-indazole (Intermediate 65) (0.50 g) N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5) (0.59 g) aqueous sodium carbonate (1M, 2.35 ml) and PdCl2dppf (0.237 g) in 1,2-dimethoxyethane (30 ml) was stirred at reflux under nitrogen for 16 h. More sodium carbonate (2.3 ml) and catalyst (120 mg) were added and reflux was continued for a further 4 h. Conc. hydrochloric acid (1 ml) was added and the mixture was heated for a further 1 h. The mixture was absorbed onto silica then purified by column chromatography on silica eluting with cyclohexane:ethyl acetate (2:1 to 1:4) to give the title compound (0.25 g).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.N1C=CC(CCCO)=CC=1>>[ClH:28].[N:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])=[CH:33][CH:34]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: ClCCCc1ccncc1
Agent: Cl
Agent: OCCCc1ccncc1
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCc3ccncc3)cc12

Procedure:
6-(3-Pyridin-4-yl-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 10% overall yield using the method described in example 85, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 81A) and 4-(3-Chloro-propyl)-pyridine hydrochloride, prepared from 4-pyridine propanol (U.S. Pat. No. 6,362,336).
Reaction SMILES: [CH3:1][O:2][CH2:3][S:4][CH:5]1[N:8]([C:9](=[C:23](O)[CH3:24])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:26])[CH:6]1[NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CS(Cl)(=O)=O.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.[Br:49]N1C(=O)CCC1=O>O1CCCC1.O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][S:4][CH:5]1[N:8]([C:9](=[C:23]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[CH2:24][Br:49])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:26])[CH:6]1[NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[CH3:1][O:2][CH2:3][S:4][CH:5]1[N:8]([C:9](=[C:23]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[CH3:24])[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C:7](=[O:26])[CH:6]1[NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C1COCCN1
Reactant: COCSC1C(NC(=O)COc2ccccc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C(C)O
Reactant: O=C1CCC(=O)N1Br
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COCSC1C(NC(=O)COc2ccccc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C(C)N1CCOCC1
Product: COCSC1C(NC(=O)COc2ccccc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C(CBr)N1CCOCC1
Reaction time: 0.5 h
Yield: 14 %
Yield: 52 %

Procedure:
One dissolves p-nitrobenzyl α-[4-methoxymethylthio-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-α-(1-hydroxyethylidene)acetate (1.06 g) in tetrahydrofuran (10 ml), cools to -40° C. under nitrogen atmosphere, adds triethylamine (489 mg) dissolved in tetrahydrofuran (1 ml) and methanesulfonyl chloride (252 mg) dissolved in tetrahydrofuran (1 ml), and stirs for 30 minutes at -40° C. and for 45 minutes at 0° C. To this solution, one adds morpholine (209 mg) dissolved in tetrahydrofuran (1 ml), keeps at 0° C. for 2 hours, adds N-bromosuccinimide (392 mg), keeps at 0° C. for 1.5 hours, adds water, and removes the separated oily material, and extracts with ethyl acetate. The extract solution and the removed oily material is combined, dried over magnesium sulfate, and evaporated. Purification of the obtained residual oil (1.4 g) by chromatography over silica gel containing 5% water (20 g) gives p-nitrobenzyl α-[4-methoxymethylthio-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-α-(1-morpholino-2-bromoethylidene)acetate (700 mg; Yield: 52%) and p-nitrobenzyl α-[4-methoxymethylthio-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-α-(1-morpholinoethylidene)acetate (170 mg; Yield: 14%).
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[ClH:1].[C:2]1([N:8]([CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[(4-amidinophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide-hydrochloride and sodium hydroxide solution.
Reaction SMILES: CO[CH:3]([O:14]C)[C:4]1[CH:5]=[C:6]([CH3:13])[C:7]([CH:11]=O)=[N:8][C:9]=1[CH3:10].[S:16]1C[C:19](=[O:21])[NH:18][C:17]1=[O:22].N1CCCCC1.Cl>C(O)C.O>[CH:3]([C:4]1[CH:5]=[C:6]([CH3:13])[C:7](=[C:11]2[S:16][C:17](=[O:22])[NH:18][C:19]2=[O:21])[NH:8][C:9]=1[CH3:10])=[O:14]
Reactant: O=C1CSC(=O)N1
Reactant: COC(OC)c1cc(C)c(C=O)nc1C
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: CCO
Product: CC1=CC(C=O)=C(C)NC1=C1SC(=O)NC1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 68.7 %

Procedure:
To a mixture of 5-dimethoxymetyl-3,6-dimethyl-2-pyridinecarboxaldehyde (53 mg, 0.25 mmol) and 2,4-thiazolidindione (44 mg, 0.38 mmol) in ethanol (5 mL) was added piperidine (0.038 mL, 0.38 mmol), and the mixture was heated to reflux for 16 h. Hydrochloric acid (1 mol/L; 0.4 mL) and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried on anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue were added tetrahydrofuran (4 mL) and hydrochloric acid (1 mol/L; 0.5 mL), and the mixture was stirred at room temperature for 7 h. Water was added, and the precipitated products were collected by filtration to afford 5-formyl-3,6-dimethylpyridin-2-ylidene-2,4-thiazolidinedione (43 mg, 66%).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[C:17]1([CH3:31])[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:18]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:19]3[CH:18]=[C:17]([CH3:31])[CH:22]=[CH:21][CH:20]=3)=[O:29])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=413.05.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[OH:1][C@@H:2]([CH2:3][N:25]1[CH2:26][CH2:27][N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][CH2:24]1)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1
Reactant: NC(=O)Nc1ccc(OC[C@@H]2CO2)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: NC(=O)Nc1ccc(OC[C@@H](O)CN2CCN(c3ccccc3)CC2)cc1
Temperature: 70 °C
Yield: 70.8 %

Procedure:
A mixture of 0.1 g of (S)-1-(4-(oxiran-2-ylmethoxy)phenyl)urea, 0.14 g of N-phenyl-piperazine, and 6 mL of abosolute ethanol was heated to 70° C. for 20 hrs. The reaction was cooled, and the resulting precipitate collected by filtration. The solids were washed three times with ethanol, and dried. 0.126 g of the title compound was obtained as a fluffy white powder was obtained. 1H NMR (d6-DMSO): δ 2.36 (dd, 1H, J=6 Hz, J=13 Hz), 2.48 (m, 1H), 2.55 (m, 4H), 3.08 (t, 4H, J=5 Hz), 3.78 (dd, 1H, J=6 Hz, J=9 Hz), 3.89 (m, 1H), 3.93 (m, 1H), 4.84 (d, 1H, J=5 Hz), 5.68 (s, 2H), 6.73 (t, 1H, J=8 Hz), 6.78 (d, 2H, J=9 Hz), 6.88 (d, 2H, J=8 Hz), 7.16 (t, 2H, J=8 Hz), 7.24 (d, 2H, J=9 Hz), 8.27 (s, 1H); MS: 371 (M+H); HRMS: Observed: 371.20723; HPLC: 100% peak area composition; retention time=6.64 min.